Matrix metalloproteinase inhibitors

ABSTRACT

The present invention relates to compounds of Formula (I): 
                         
pharmaceutically acceptable salts thereof, corresponding preparation processes, pharmaceutical formulations and methods for use as inhibitors of matrix metalloproteinase enzymes (MMPs).

CROSS REFERENCE TO PRIOR APPLICATIONS

This application is a continuation of U.S. application Ser. No.10/571,443, which was filed Mar. 13, 2006 now U.S. Pat. No. 7,601,729,which is a 371 Application of PCT/EP2004/010319, which was filed Sep.10, 2004, which claims priority to GB0321538.1, which was filed Sep. 13,2003.

FIELD OF THE INVENTION

This invention relates to novel chemical compounds, processes for theirpreparation, pharmaceutical formulations containing them and their usein therapy.

The compounds of the invention are inhibitors of matrixmetalloproteinase enzymes (MMPs).

BACKGROUND OF THE INVENTION

Matrix metalloproteinase enzymes play a major role in extracellularmatrix component degradation and remodelling. Examples of MMPs includecollagenase 1, 2 and 3, gelatinase A and B, stromelysin 1, 2 and 3,matrilysin, macrophage metalloelastase, enamelysin and membrane type 1,2, 3 and 4 MMP. The enzymes are secreted by connective tissue cells andinflammatory cells. Enzyme activation can not only initiate tissuedamage but induce increased inflammatory cell infiltration into thetissue, leading to more enzyme production and subsequent tissue damage.For example, elastin fragments produced by MMP degradation are believedto stimulate inflammation by attracting macrophages to the site of MMPactivity. Inhibition of MMPs provides a means for treating diseasestates wherein inappropriate metalloprotease activity results indegradation of connective tissue and inflammation.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect, the present invention provides compounds of formula (I):

Wherein:A represents bond, C₁₋₆alkyl or CH═CH—C₁₋₄alkyl;B represents bond, O, S, SO, SO₂, CO, CR⁷R⁸, CO₂R¹⁴, CONR¹⁴R¹⁵,N(COR¹⁴)(COR¹⁵), N(SO₂R¹⁴)(COR¹⁵) or NR¹⁴R¹⁵;D represents bond, or C₁₋₆alkyl;E represents substituted aryl or substituted or unsubstitutedheteroaryl;Q represents an optionally substituted 5- or 6-membered aryl orheteroaryl ring;X represents O, S, SO, SO₂, CO, CNR⁵, CNOR⁵, CNNR⁵R⁶, NR¹¹ or CR⁷R⁸;Y represents CR⁵OR¹¹, CR⁵SR¹¹, NOR⁵, CR⁵NR⁶R¹¹, SO, SO₂, CO, CNR⁵, CNOR⁵or CS;R¹ and R^(1′) each independently represents H, C₁₋₆alkyl orC₁₋₄alkylaryl;R² represents CO₂R¹², CH₂OR¹² or CONR¹²R¹³, CONR¹²OR¹³, NR¹²COR¹³,SR¹²PO(OH)₂, PONHR¹² or SONHR¹²;R³ represents H, C₁₋₆alkyl or C₁₋₄alkylaryl;R⁴ represents optionally substituted aryl or heteroaryl;Z represents a bond, CH₂, O, S, SO, SO₂, NR⁵, OCR⁵R⁶, CR⁹R¹⁰O or Z, R⁴and Q together form an optionally substituted fused tricyclic group;R⁵ and R⁶ each independently represent H, C₁₋₆ alkyl or C₁₋₄ alkylaryl;R⁷ and R⁸ each independently represent H, halo, C₁₋₆ alkyl or C₁₋₄alkylaryl;R⁹ and R¹⁰ each independently represents H, C₁₋₆ alkyl optionallysubstituted by halo, cyano, OR¹¹ or NR⁶R¹¹, C₁₋₄ alkylaryl optionallysubstituted by halo, cyano, OR11 or NR⁶R¹¹, OR¹¹ or, together with the Nto which they are attached, R⁹ and R¹⁰ form a heterocyclic groupoptionally containing one or more further heteroatoms selected from O, Nand S;R¹¹ represents H, C₁₋₆ alkyl, C₁₋₄ alkylaryl or COR⁵;R¹² and R¹³ each independently represent H, C₁₋₃ alkyl, C₁₋₃ alkylarylor C₁₋₃ alkylheteroaryl or, together with the functionality to whichthey are attached, R¹² and R¹³ form a heterocyclic group optionallycontaining one or more further atoms selected from C, O, N and S;R¹⁴ and R¹⁵ each independently represent H, C₁₋₆ alkyl, C₁₋₄ alkylarylor C₁₋₄ alkylheteroaryl or together with the functionality to which theyare attached R¹⁴ and R¹⁵ form a heterocyclic or fused heterocyclic groupwhich may contain one or more further atoms selected from C, O, N and S;and physiologically functional derivatives thereof.

References to ‘aryl’ include references to monocyclic carbocyclicaromatic rings (e.g. phenyl) and bicyclic carbocyclic aromatic rings(e.g. naphthyl) and references to ‘heteroaryl’ include references tomono- and bicyclic heterocyclic aromatic rings containing 1-3 heteroatoms selected from nitrogen, oxygen and sulphur. In a bicyclicheterocyclic aromatic group there may be one or more hetero-atoms ineach of the rings, or only in one ring. Examples of monocyclicheterocyclic aromatic rings include pyridinyl, pyrimidinyl, thiophenyl,furanyl, pyrrolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,thiadiazolyl, uracil or imidazolyl, and examples of bicyclicheterocyclic aromatic rings include benzofuranyl, benzimidazolyl,quinolinyl or indolyl. Carbocyclic and heterocyclic aromatic rings maybe optionally substituted, e.g. by one or more C₁₋₆ alkyl, C₂₋₆ alkenyl,halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂, —NHCOC₁₋₆alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃, —CONR6R7—SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups, or by fused cycloalkyl orheterocyclic rings which may themselves be substituted, for example bycarbonyl groups.

References to ‘alkyl’ include references to both straight chain andbranched chain aliphatic isomers of the corresponding alkyl. It will beappreciated that references to alkylene and alkoxy shall be interpretedsimilarly.

Suitably A represents bond or C₁₋₆ alkyl, such as C₂ or C₃ alkyl.

Suitably B represents bond.

Suitably D represents methylene or bond, preferably bond.

For Example A-B-D may suitably represent —CH₂CH₂—.

Optional substituents for E include one or more of C₁₋₆ alkyl, C₂₋₆alkenyl, halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂,—NHCOC₁₋₆ alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃,—CONR⁵R⁶—SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups, or by fused cycloalkyl orheterocyclic rings which may themselves be substituted, for example bycarbonyl groups.

In one subgroup of compounds according to the invention, E representssubstituted or unsubstituted 5- or 6-membered heteroaryl such as anitrogen-containing heteroaromatic group, for example, uracil.

In a further subgroup of compounds according to the invention, Erepresents aryl, such as phenyl, substituted by a fused substituted orunsubstituted heterocyclic ring, such as a nitrogen-containingheterocyclic ring. Exemplary of this subgroup are compounds according tothe invention wherein E represents phthalimido.

Suitable optional substituents for Q include one or more of C₁₋₆ alkyl,C₂₋₆ alkenyl, halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino,—N(CH₃)₂, —NHCOC₁₋₆ alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃,—CONR⁵R⁶—SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups. Most suitably Q representsunsubstituted phenyl.

Suitably, R¹ and R^(1′) each represents hydrogen.

Suitably R² represents CO₂R¹², such as CO₂H.

Suitably R³ represents hydrogen.

Suitably R⁴ benzofuranyl, phenyl or pyrimidinyl. Suitable optionalsubstituents for R⁴ include one or more of C₁₋₆ alkyl, C₂₋₆ alkenyl,halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂, —NHCOC₁₋₆alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃, —CONR⁵R⁶,—SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups. Preferably R⁴ representsoptionally substituted phenyl or optionally substituted pyrimidinyl.

Suitably X represents CH₂.

Suitably Y represents CHOR¹¹, where R¹¹ suitably represents H, C₁₋₆alkyl or COR⁵. Preferably R¹¹ represents H. R⁵ preferably representsC₁₋₆ alkyl.

Suitably Z represents a bond, or Z, R4 and Q together represent a fusedtricyclic group. Preferably, Z represents a bond.

A subgroup of compounds of formula (I) is presented by formula (Ia) andformula (Ib):

wherein:

T is absent or represents O, S, NR¹⁶ or CR¹⁶R¹⁷;

--- represents optional bonds;

G¹ and G² each independently represents CH or N;

A represents bond, C₁₋₆alkyl or CH═CH—C₁₋₄alkyl;

B represents bond, 0, S, SO, SO₂, CO, CR⁷R⁸, CO₂R¹⁴, CONR¹⁴R¹⁵,N(COR¹⁴)(COR¹⁵), N(SO₂R¹⁴)(COR¹⁵), NR¹⁴R¹⁵;

D represents bond, or C₁₋₆ alkyl;

E represents substituted aryl or substituted or unsubstitutedheteroaryl;

R¹⁶ represents H, C₁₋₆ alkyl or C₁₋₄ alkylaryl;

R¹⁷ represents H or C₁₋₆ alkyl;

R¹⁸ and R¹⁹ each independently represents halo, cyano, nitro, OR¹⁶,SR¹⁶, COR¹⁶, NR¹⁷COR¹⁶, CONR¹⁶R¹⁷, optionally substituted phenoxy orC₁₋₆alkyl optionally substituted by OR¹⁶;

m and n each independently represents 0 or an integer 1, 2 or 3; andphysiologically functional derivatives thereof.

In compounds of formulae (Ia) and (Ib), A suitably represents alkyl,such as C₁₋₄alkyl, for example ethyl. Suitably, B represents bond.Suitably D represents bond. Suitably E represents substituted orunsubstituted heteroaryl such as nitrogen-containing heteroaryl, forexample uracil, or E represents phenyl substituted by a fusedsubstituted or unsubstituted heterocyclic ring, such as phthalimido.

Preferably n is 0 and m is 1.

Preferably R¹⁸ represents a para-substituent selected from NO₂, C₁₋₆alkyl, C₁₋₆ alkoxy, halo, SC₁₋₆ alkyl, CN and COC₁₋₆ alkyl.

Preferably, G¹ and G² are both CH or both N.

A further subgroup of compounds according to the invention isrepresented by compounds of formula (Ic):

wherein A,B,D,E,R¹⁸ and m are as defined for formulae (Ia) and (Ib)above; and physiologically functional derivatives thereof.

In compounds of formula (Ic), A-B-D suitably represents —CH₂—CH₂—.Suitably m represents 0 or 1. When m is 1, R¹⁸ suitably represents apara substituent selected from NO₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo, SC₁₋₆alkyl, CN, OCF₃, or COC₁₋₆ alkyl.

A further subgroup of compounds according to the invention isrepresented by compounds of formula (Id):

wherein R²⁰ represents a substituted or unsubstituted aryl or heteroarylgroup selected from phenyl, benzofuraryl and pyrimidinyl; and

represents a substituted aryl or a substituted or unsubstitutedheteroaryl group comprising at least one nitrogen atom; andphysiologically functional derivatives thereof.

In compounds of formula (Id), R²⁰ suitably represents unsubstituted orsubstituted phenyl, unsubstituted benzofuraryl or unsubstitutedpyrimidinyl. When R²⁰ represents substituted phenyl, suitably the phenylring will be substituted by a single substituent in the para position.Suitable substituents include C₁₋₆alkyl, C₂₋₆alkenyl, halogen,C₁₋₆alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂, —NHCOC₁₋₆alkyl,—OCF₃, —CF₃, —CO₂C₁₋₆alkyl, OCHCF₂, —SCF₃, —CONR⁵R⁶, —SO₂N(CH₃)₂,—SO₂CH₃ or —SCH₃, such as cyano, COCH₃, OCF₃ and SCH₃.

By the term “physiologically functional derivative” is meant a chemicalderivative of a compound of formula (I) having the same physiologicalfunction as the free compound of formula (I), for example, by beingconvertible in the body thereto and includes any pharmaceuticallyacceptable esters, amides and carbamates, salts and solvates ofcompounds of formula (I) which, upon administration to the recipient,are capable of providing (directly or indirectly) compounds of formula(I) or active metabolite or residue thereof.

Suitable salts of the compounds of formula (I) include physiologicallyacceptable salts and salts which may not be physiologically acceptablebut may be useful in the preparation of compounds of formula (I) andphysiologically acceptable salts thereof. If appropriate, acid additionsalts may be derived from inorganic or organic acids, for examplehydrochlorides, hydrobromides, sulphates, phosphates, acetates,benzoates, citrates, succinates, lactates, tartrates, fumarates,maleates, 1-hydroxy-2-naphthoates, palmoates, methanesulphonates,formates or trifluoroacetates.

Examples of Solvates Include Hydrates.

When compounds of formula (I) contain chiral centres, the inventionextends to mixtures of enantiomers (including racemic mixtures) anddiastereoisomers as well as to individual enantiomers. Generally it ispreferred to use a compound of formula (I) in the form of a purifiedsingle enantiomer. Enantiomerically pure compounds of formula (I) areavailable by way of chirally selective synthesis or by way of chiralseparation.

The compounds of formula (I) and salts and solvates thereof may beprepared by the methodology described hereinafter, constituting afurther aspect of this invention.

A first process (A) according to the invention for preparing a compoundof formula (I) wherein Z represents a bond comprises reacting a compoundof formula (II):

wherein R¹, R^(1′), R², R³, R^(3′), A, B, D, E, Q, X and Y are aspreviously defined for formula (I) and L represents a leaving group,with a reagent suitable to introduce the group R⁴, such as a compoundR⁴B(OH)₂, suitably in the presence of a catalyst, such as a noble metalcatalyst e.g. palladium, and a suitable base, such as an alkali metalcarbonate, e.g. caesium carbonate. The reaction is conveniently carriedout in a suitable solvent, such as a polar organic solvent, e.g.dimethyl formamide. Suitable leaving groups represented by L includehalides, especially bromide or iodide.

For example, for the synthesis of a (optionally substituted) biphenylcompound according to the invention (ie Q and R⁴ are both phenyl), aphenyl boronic acid may be reacted with[(4-bromophenyl)(methylsulfonyl)amino]acetic acid in the presence of asuitable catalyst:

A second process (B) according to the invention for preparing a compoundof formula (I) wherein Z represents O, S, SO, SO₂, or NR⁵, comprisesreacting a compound of formula (III):

wherein Q, X, Y, R¹, R^(1′), R², R³, A, B, D and E are as previouslydefined for formula (I), and T represents OH, SH or NR H, with a reagentsuitable to introduce the group R⁴, such as a compound R⁴-L, wherein Lis a suitable leaving group. The reaction is conveniently carried out ina suitable solvent, such as a solvent containing a heteroatom, e.g.pyridine in the presence of a suitable catalyst, for example a palladiumcatalyst (preferred for T=NR⁵H) or a copper catalyst (preferred for T=OHor SH). Suitable leaving groups represented by L include halides,especially bromide or iodide.

For compounds in which Z represents SO or SO₂, the compound of formula(I) may conveniently be prepared by initial preparation of the compoundin which Z represents S, followed by oxidation of the sulphide to thesulfoxide or the sulfone. The oxidation step may be carried out usingmethods known in the art such as oxidation with hydrogen peroxide in thecase of the sulfone, or oxidation with Oxone® (potassiumperoxymonosulfate) in the case of the sulfoxide.

A third process (C) according to the invention for preparing a compoundof formula (I) wherein Z represents OCR⁵R⁶, comprises reacting acompound of formula (IV):

wherein Q, X, Y, R¹, R^(1′), R², R³, R⁵, R⁶, A, B, D and E are aspreviously defined for formula (I), with a reagent suitable to introducethe group R⁴—O such as a compound R⁴—OH. The reaction is convenientlycarried out in a suitable solvent, such as an alcohol solvent, e.g.ethanol, under basic conditions, for example in the presence of anaqueous hydroxide such as sodium hydroxide. Suitable leaving groupsrepresented by L include halides, especially bromide or iodide.

A fourth process (D) according to the invention for preparing a compoundof formula (I) wherein Z represents CR⁵R⁶O, comprises reacting acompound of formula (V):

wherein Q, X, Y, R¹, R^(1′), R², R³, A, B, D and E are as previouslydefined for formula (I), with a reagent suitable to introduce the groupR⁴CR⁵R⁶ such as a compound R⁴CR⁵R⁶-L, wherein L is a suitable leavinggroup. The reaction is conveniently carried out in a suitable solvent,such as an alcohol solvent, e.g. ethanol, under basic conditions, forexample in the presence of an aqueous hydroxide such as sodiumhydroxide. Suitable leaving groups represented by L include halides,especially bromide or iodide.

A fifth process (E) according to the invention for preparing a compoundof formula (I) wherein Z represents CH₂, comprises reacting a compoundof formula (VI):

wherein Q, X, Y, R¹, R^(1′), R², R³, A, B, D and E are as previouslydefined for formula (I), with a reagent suitable to introduce the groupR⁴CH₂, such as a compound R⁴CH₂-L, wherein L is a suitable leavinggroup, for example halide, suitably in the presence of a catalyst, forexample a Lewis acid catalyst such as AlCl₃. A Friedel-Crafts reactionmay accordingly be appropriate.

A sixth process (F) according to the invention for preparing a compoundof formula (I) comprises reacting a compound of formula (VII)

wherein Q, X, Y, R¹, R^(1′), R², R³, R⁴, A, B and D are as previouslydefined for formula (I), with a reagent suitable to introduce the groupE such as a compound H-E. The reaction is conveniently carried out in asuitable solvent, such as an aprotic solvent, e.g. dimethylformamide,under basic conditions, for example in the presence of a base such aspotassium hydride. Suitable leaving groups represented by L includehalides, such as bromide or iodide, and methylsulphonyloxy groups.

A seventh process (G) according to the invention comprises carrying outa process selected from processes (A) to (F) followed by interconversionof one or more functional groups. Interconversion processes includeprocesses such as oxidation, reduction, substitution, deprotection etc.,standard in the art of synthetic chemistry.

Compounds of formula (II), (III), (IV), (V) and (VI) may be prepared byreaction of compounds of formula (VIII):

wherein Q, X, Y, R¹, R^(1′), R², R³, A, B and D are as previouslydefined for formula (I) and U is L in the case of compound (II), T inthe case of compound (III), L(R⁵)(R⁶)CH₂ in the case of compound (IV),OH in the case of compound (V) and H in the case of compound (VI), andL² represents a leaving group more labile than L, with a compound offormula E-H or a salt of formula E⁻M⁺. Suitable leaving groupsrepresented by L² include halides, such as bromide or iodide, andmethylsulphonyloxy groups. Alternatively, an activated leaving group L²of the Mitsunobu type may be generated by reacting a correspondingalcohol with diisopropylazodicarboxylate and triphenylphosphine; thatleaving group may then be displaced by an anion E⁻M⁺ to generate theproduct.

Compounds of formula (VIII) may in turn be prepared by reaction ofcompounds of formula (IX):

wherein Q, X, Y, R¹, R^(1′), R² and R³ are as previously defined forformula (I), U is as previously defined for formula (VIII) and L³represents a leaving group, with a compound of formula H-A-B-D-L². Thereaction is conveniently carried out in a suitable solvent, such as anaprotic solvent, e.g. dimethylformamide in the presence of a suitablecatalyst, for example a metal hydride.

Compounds of formula (IX) may in turn be prepared by reaction ofcompounds of formula (X) with compounds of formula (XI):

wherein Q, X, Y, R¹, R^(1′), R² and R³ are as previously defined forformula (I), U is as previously defined for formula (VIII), L³ is aspreviously defined for formula (IX), and L⁴ represents a leaving group.The reaction is conveniently carried out in a suitable solvent, such asan aprotic solvent, e.g. tetrahydrofuran in the presence of a suitablecatalyst, for example a metal hydride.

Analogously, compounds of formula (VII) may be prepared by reaction ofcompounds of formula (XII):

wherein Q, X, Y, R¹, R^(1′), R², R³ and R⁴ are as previously defined forformula (VII), and L³ represents a leaving group, with a compound offormula H-A-B-D-L. The reaction is conveniently carried out in asuitable solvent, such as an aprotic solvent, e.g. dimethylformamide inthe presence of a suitable catalyst, for example a metal hydride.

Compounds of formula (XII) may in turn be prepared by reaction ofcompounds of formula (XIII) with compounds of formula (XIV):

wherein Q, X, Y, R¹, R^(1′), R², R³ and R⁴ are as previously defined forformula (I) L³ is as previously defined for formula (XII), and L⁴represents a leaving group. The reaction is conveniently carried out ina suitable solvent, such as an aprotic solvent, e.g. tetrahydrofuran inthe presence of a suitable catalyst, for example a metal hydride.

Compounds of formula R⁴B(OH)₂, R⁴-L, R⁴—OH, R⁴CR⁵R⁶-L, R⁴—CH₂-L, H-E,H-A-B-D-L², (X), (XI), (XIII) and (XIV) are known or may be preparedfrom known compounds by methods familiar to those skilled in the art.

Depending on the identity of the group X, group Y, group R², L, L², L³and L⁴ it may be preferable for one or more of those groups to beprotected during one or more steps of the synthesis of a compound offormula (I). Suitable protecting groups are known to those skilled inthe art. Protecting groups may be any conventional protecting groups,for example as described in “Protective Groups in Organic Synthesis” byTheodora Greene and Peter G. M. Wuts (John Wiley and Sons Inc. 1999).

Enantiomeric compounds of the invention may be obtained (a) by theseparation of the components of the corresponding racemic mixture, forexample, by chiral chromatography, enzymatic resolution methods orpreparing and separating suitable diastereoisomers, (b) by directsynthesis from the appropriate chiral starting materials by the methodsdescribed above, or (c) by methods analogous to those described aboveusing chiral reagents.

Optional conversion of a compound of formula (I) to a corresponding saltmay conveniently be effected by reaction with the appropriate acid orbase. Optional conversion of a compound of formula (I) to acorresponding solvate or other physiologically functional derivative maybe effected by methods known to those skilled in the art.

Compounds of formula (I) may be useful for the treatment of anyconditions in which inhibition of matrix metalloproteinase would bebeneficial, especially in the treatment of inflammatory diseases andautoimmune disorders.

Examples of inflammatory conditions and autoimmune disorders in whichthe compounds of the invention have potentially beneficial effectsinclude diseases of the respiratory tract such as asthma (includingallergen-induced asthmatic reactions), cystic fibrosis, bronchitis(including chronic bronchitis), chronic obstructive pulmonary disease(COPD), adult respiratory distress syndrome (ARDS), chronic pulmonaryinflammation, rhinitis and upper respiratory tract inflammatorydisorders (URID), ventilator induced lung injury, silicosis, pulmonarysarcoidosis, idiopathic pulmonary fibrosis, bronchopulmonary dysplasia,arthritis, e.g. rheumatoid arthritis, osteoarthritis, infectiousarthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis,Reiter's syndrome, gouty arthritis and prosthetic joint failure, gout,acute synovitis, spondylitis and non-articular inflammatory conditions,e.g. herniated/ruptured/prolapsed intervertebral disk syndrome,bursitis, tendonitis, tenosynovitic, fibromyalgic syndrome and otherinflammatory conditions associated with ligamentous sprain and regionalmusculoskeletal strain, inflammatory disorders of the gastrointestinaltract, e.g. ulcerative colitis, diverticulitis, Crohn's disease,inflammatory bowel diseases, irritable bowel syndrome and gastritis,multiple sclerosis, systemic lupus erythematosus, scleroderma,autoimmune exocrinopathy, autoimmune encephalomyelitis, diabetes, tumorangiogenesis and metastasis, cancer including carcinoma of the breast,colon, rectum, lung, kidney, ovary, stomach, uterus, pancreas, liver,oral, laryngeal and prostate, melanoma, acute and chronic leukemia,periodontal disease, neurodegenerative disease, Alzheimer's disease,Parkinson's disease, epilepsy, muscle degeneration, inguinal hernia,retinal degeneration, diabetic retinopathy, macular degeneration, ocularinflammation, bone resorption diseases, osteoporosis, osteopetrosis,graft vs. host reaction, allograft rejections, sepsis, endotoxemia,toxic shock syndrome, tuberculosis, usual interstitial and cryptogenicorganizing pneumonia, bacterial meningitis, systemic cachexia, cachexiasecondary to infection or malignancy, cachexia secondary to acquiredimmune deficiency syndrome (AIDS), malaria, leprosy, leishmaniasis, Lymedisease, glomerulonephritis, glomerulosclerosis, renal fibrosis, liverfibrosis, pancreatitis, hepatitis, endometriosis, pain, e.g. thatassociated with inflammation and/or trauma, inflammatory diseases of theskin, e.g. dermatitis, dermatosis, skin ulcers, psoriasis, eczema,systemic vasculitis, vascular dementia, thrombosis, atherosclerosis,restenosis, reperfusion injury, plaque calcification, myocarditis,aneurysm, stroke, pulmonary hypertension, left ventricular remodelingand heart failure.

Diseases of principal interest include COPD and inflammatory diseases ofthe respiratory tract and joints and vascular diseases.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished conditions.

There is thus provided as a further aspect of the invention a compoundof formula (I) or a physiologically acceptable derivative thereof foruse in medicine.

According to another aspect of the invention, there is provided the useof a compound of formula (I) or a physiologically acceptable derivativethereof for the manufacture of a medicament for the treatment ofinflammatory conditions or autoimmune disorders.

In a further or alternative aspect there is provided a method for thetreatment of a human or animal subject suffering from or susceptible toan autoimmune disorder or an inflammatory condition which methodcomprises administering to said human or animal subject an effectiveamount of a compound of formula (I) or a physiologically functionalderivative thereof.

The compounds according to the invention may be formulated foradministration in any convenient way, and the invention therefore alsoincludes within its scope pharmaceutical compositions comprising acompound of formula (I) or a physiologically acceptable derivativethereof together, if desirable, with one or more physiologicallyacceptable diluents or carriers.

There is also provided a process for preparing such a pharmaceuticalformulation which comprises mixing the ingredients.

The compounds according to the invention may, for example, be formulatedfor oral, inhaled, intranasal, topical, buccal, parenteral or rectaladministration, preferably for oral administration.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, mucilage of starch, cellulose or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose,sugar, maize-starch, calcium phosphate or sorbitol; lubricants, forexample, magnesium stearate, stearic acid, talc, polyethylene glycol orsilica; disintegrants, for example, potato starch, croscarmellose sodiumor sodium starch glycollate; or wetting agents such as sodium laurylsulphate. The tablets may be coated according to methods well known inthe art. Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, ormay be presented as a dry product for constitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitolsyrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethylcellulose, carboxymethyl cellulose, aluminium stearate gel orhydrogenated edible fats; emulsifying agents, for example, lecithin,sorbitan mono-oleate or acacia; non-aqueous vehicles (which may includeedible oils), for example almond oil, fractionated coconut oil, oilyesters, propylene glycol or ethyl alcohol; or preservatives, forexample, methyl or propyl p-hydroxybenzoates or sorbic acid. Thepreparations may also contain buffer salts, flavouring, colouring and/orsweetening agents (e.g. mannitol) as appropriate.

Compounds according to the invention for topical administration may beformulated as creams, gels, ointments or lotions or as a transdermalpatch. Such compositions may for example be formulated with an aqueousor oily base with the addition of suitable thickening, gelling,emulsifying, stabilising, dispersing, suspending, and/or colouringagents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents, thickening agents, or colouringagents. They may also contain a preservative.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in conventional manner.

The compounds may also be formulated as suppositories, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds according to the invention may also be formulated forparenteral administration by bolus injection or continuous infusion andmay be presented in unit dose form, for instance as ampoules, vials,small volume infusions or pre-filled syringes, or in multi-dosecontainers with an added preservative. The compositions may take suchforms as solutions, suspensions, or emulsions in aqueous or non-aqueousvehicles, and may contain formulatory agents such as anti-oxidants,buffers, antimicrobial agents and/or tonicity adjusting agents.Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g. sterile, pyrogen-free water,before use. The dry solid presentation may be prepared by filling asterile powder aseptically into individual sterile containers or byfilling a sterile solution aseptically into each container andfreeze-drying.

The pharmaceutical compositions according to the invention may also beused in combination with other therapeutic agents, for exampleanti-inflammatory agents (such as corticosteroids (e.g. fluticasonepropionate, beclomethasone dipropionate, mometasone furoate,triamcinolone acetonide or budesonide) or NSAIDs (e.g. sodiumcromoglycate, nedocromil sodium, PDE-4 inhibitors, leukotrieneantagonists, CCR-3 antagonists, iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine 2a agonists)) orbeta adrenergic agents (such as salmeterol, salbutamol, formoterol,fenoterol or terbutaline and salts thereof) or antiinfective agents(e.g. antibiotics, antivirals).

It will be appreciated that when the compounds of the present inventionare administered in combination with other therapeutic agents normallyadministered by the inhaled or intranasal route, that the resultantpharmaceutical composition may be administered by the inhaled orintranasal route.

Compounds of the invention may conveniently be administered in amountsof, for example, 0.01 to 100 mg/kg body weight, preferably 0.1 to 25mg/kg body weight, more preferably 0.3 to 5 mg/kg body weight. Thecompounds may be given more than once daily to be equivalent to thetotal daily dose. The precise dose will of course depend on the age andcondition of the patient and the particular route of administrationchosen and will ultimately be at the discretion of the attendantphysician.

No toxicological effects are expected when a compound according to thepresent invention is administered in the above mentioned dose range.

Compounds of the invention may be tested for in vitro activity inaccordance with the following assay:

The fluorescent peptide substrate used in the MMP-12 assay isFAM-Gly-Pro-Leu-Gly-Leu-Phe-Ala-Arg-Lys(TAMRA) (SEQ. ID No. 1), whereFAM represents carboxyfluorescein, and TAMRA representstetramethylrhodamine. MMP12 catalytic domain (residues 106-268) proteinwas expressed in E. coli in the form of insoluble inclusion bodies &stored in concentrated solution under denaturing conditions (8Mguanidine hydrochloride). Enzyme was refolded into active form in situby direct dilution into assay reactions. The 51 uL reactions are run inNUNC-brand black, square 384-well plates, each well containing 2 uMsubstrate, 20 nM enzyme, and 0.001-100 uM inhibitor, in 50 mM HEPES, pH7.5, 150 mM NaCl, 10 mM CaCl₂, 1 uM ZnAc, 0.6 mM CHAPS, and 2% DMSO.Positive control wells contain no inhibitor. Negative control wells areeffected by either pre-dispensing the EDTA quench (see below) or byomiting enyme. Reactions are incubated at ambient temperature for 120min, then quenched by the addition of 15 uL of 100 mM EDTA. Productformation in each well is quantified by measuring flourescense with aMolecular Devices Acquest. The excitation wavelength is set at 485 nM,and the emission wavelength is 530 nM. IC₅₀ values were obtained byfirst calculating the percent inhibition (% I) at each inhibitorconcentration (% I=100*(1−(I−C2)/(C1−C2)), where C1 is the mean of thepositive controls, and C2 is the mean of the negative controls), thenfitting the % I vs. inhibitor concentration [I] data to: %I=A+((B−A)/(1+((C/[I]^D))), where A is the lower asymptote, B is theupper asymptote, C is the IC₅₀ value, and D is the slope factor. Whentested in this assay, compounds of Examples 1 to 12 had IC₅₀s below 100micromolar.

The invention may be illustrated by reference to the following examples,which should not be construed as a limitation thereto:

General Experimental Details

LC/MS data were obtained under the following conditions:

-   -   Column: 3.3 cm×4.6 mm ID, 3 um ABZ+PLUS    -   Flow Rate: 3 ml/min    -   Injection Volume: 5 μl    -   Temp: RT    -   UV Detection Range: 215 to 330 nm        Solvents: A: 0.1% Formic Acid+10 mMolar Ammonium Acetate.    -   B: 95% Acetonitrile+0.05% Formic Acid

Gradient: Time A % B % 0.00 100 0 0.70 100 0 4.20 0 100 5.30 0 100 5.50100 0

¹HNMR spectra were obtained at 400 MHz on a Bruker-SpectrospinUltrashield 400 spectrophotometer.

EXAMPLES Example 15-Biphenyl-4-yl-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoicacid

Potassium phthalimide (8.8 mg, 60 μmol) was added in one portion to astirred solution of 1,1-dimethylethyl5-(4-biphenylyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate(28.4 mg, 50 μmol) in dimethylformamide (0.5 mL) under nitrogen at roomtemperature. The resulting solution was heated at 80° C. for 1 h 45 minthen cooled to room temperature. The volatiles were evaporated and theresidue taken up in dichloromethane (0.5 mL). Trifloroacetic acid (0.5mL) was added in one portion and the resulting solution stirred for 1 hat room temperature. The volatiles were evaporated and the residuepurified by mass directed auto-preparative HPLC to give the titlecompound as a white solid (6.0 mg, 27%). LC/MS: 3.43 min; z/e 444, calcd(M+1) 444. ¹H NMR (400 MHz: CDCl₃): 7.85 (2H), 7.70 (2H), 7.55 (1H),7.50 (1H), 7.45 (2H), 7.30 (1H), 7.25 (4H), 3.85 (3H), 2.95 (1H), 2.75(1H), 2.60 (1H), 2.20 (1H), 2.05 (1H), 1.90 (2H).

Example 25-Biphenyl-4-yl-3-hydroxy-2-[2-(3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)ethyl]pentanoicacid

Prepared by an analogous reaction sequence to example 1. LC/MS: 2.96min; Z/e 423, calcd (M+1) 423.

Example 35-Biphenyl-4-yl-3-hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl]pentanoicacid

Prepared by an analogous reaction sequence to example 1. LC/MS: 2.98min; z/e 423, calcd (M+1) 423.

Example 45-(4′-Acetylbiphenyl-4-yl)-3-hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl]pentanoicacid

A solution of3-hydroxy-5-(4-iodophenyl)-2-[2-(3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)ethyl]pentanoicacid (10 mg, 21 μmol) in dimethylformamide (0.5 mL) was added in oneportion to a mixture of p-acetylbenzeneboronic acid (4.0 mg, 25 μmol)and fibrecat FC1001 (2.71% Pd; 8.3 mg, 2.0 μmol) in a Smith microwavereaction vial. Aqueous sodium carbonate solution (1.0 M; 53 μL, 53 μmol)was added and the vial capped. The crude reaction mixture was heated at150° C. for 15 min using a Smith Synthesiser microwave reactor. Oncooling the vial was opened and the contents filtered through a Whatman5 μM filter tube, washing the filter cake with methanol (2×1 mL). Thefiltrate was evaporated and the resulting residue was purified usingmass directed auto-preparative reverse phase HPLC to give the titlecompound (6.0 mg, 61%) as a white solid. LC/MS: 2.82 min; z/e 465, calcd(M+1) 465. H NMR (400 MHz: DMSO-d₆): 8.00 (2H), 7.80 (2H), 7.60 (4H),7.30 (2H), 6.65 (1H), 3.70 (3H), 3.10 (3H), 2.80 (1H), 2.60 (2H), 2.30(1H), 1.85 (2H), 1.60 (1H).

Example 53-Hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl]-5-(4-pyrimidin-5-ylphenyl)pentanoicacid

Prepared by an analogous reaction sequence to example 4. LC/MS: 2.27min; Z/e 425, calcd (M+1) 425.

Example 63-Hydroxy-2-[2-(3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)ethyl]-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoicacid

Prepared by an analogous reaction sequence to example 4. LC/MS: 3.28min; Z/e 506, calcd (M+1) 506.

Example 75-[4-(1-Benzofuran-2-yl)phenyl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoicacid

A solution of2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-iodophenyl)pentanoicacid (25 mg, 50 μmol) in dimethylformamide (1.0 mL) was added in oneportion to a mixture of -benzofuran-2-ylboronic acid (11 mg, 70 μmol)and fibrecat FC1001 (2.71% Pd; 20 mg, 5.0 μmol) in a Smith microwavereaction vial. Cesium carbonate (41.0 mg, 125 μmol) was added and thevial capped. The crude reaction mixture was heated at 150° C. for 15 minusing a Smith Synthesiser microwave reactor. On cooling the vial wasopened and the contents partitioned between methanol/dichloromethane(10:90; 10 mL) and aqueous hydrochloric acid solution (2.0 M; 10 mL).The organic phase was separated and filtered through a Whatman 5 μMfilter tube, washing the filter cake with methanol (2×1 mL). Thefiltrate was evaporated and the resulting residue was purified usingmass directed auto-preparative reverse phase HPLC to give the titlecompound (3.0 mg, 12%) as a pale yellow solid. LC/MS: 3.69 min; z/e 484,calcd (M+1) 484. ¹H NMR (400 MHz: DMSO-d₆): 7.80 (6H), 7.65 (2H), 7.30(5H), 3.65 (1H), 3.60 (2H), 2.75 (1H), 2.55 (1H), 2.40 (1H major), 2.25(1H minor), 1.85 (2H), 1.65 (2H).

Example 82-[2-(1,3-Doxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoicacid

Prepared by an analogous reaction sequence to example 7. LC/MS: 3.72min; Z/e 528, calcd (M+1) 528.

Example 92-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4′-(methylthio)biphenyl-4-yl]pentanoicacid

Prepared by an analogous reaction sequence to example 7. LC/MS: 3.61min; z/e 490, calcd (M+1) 490.

Example 105-(4′-Cyanobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoicacid

Prepared by an analogous reaction sequence to example 7. LC/MS: 3.34min; Z/e 469, calcd (M+1) 469.

Example 115-(4′-Acetylbiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoicacid

Prepared by an analogous reaction sequence to example 7. LC/MS: 3.28min; z/e 486, calcd (M+1) 486.

Example 122-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-pyrimidin-5-ylphenyl)pentanoicacid

Prepared by an analogous reaction sequence to example 7. LC/MS: 2.70min; Z/e 446, calcd (M+1) 446.

Intermediate 1: 4-Bromomethyl-biphenyl

Carbon tetrabromide (8.99 g, 27.1 mmol) and triphenyl phosphine (7.11 g,27.1 mmol) were added to a stirred solution of biphenyl-4-yl methanol(5.00 g, 27.1 mmol) in dichloromethane (100 mL) at room temperature.Stirring was continued at room temperature for 1.5 hours then thesolvent removed by evaporation under reduced pressure. The residue waspurified by column chromatography on silica gel (1:20 diethyl ether:cyclohexane) to give the title compound (6.37 g, 95%) as a white solid.¹H NMR (400 MHz: CDCl₃): 7.6 (4H), 7.45 (4H), 7.35 (1H), 4.55 (2H).

Intermediate 2: 5-Biphenyl-4-yl-3-oxo-pentanoic acid tert-butyl ester

A solution of t-butyl acetoaceate (1.84 mL, 11.1 mmol) intetrahydrofuran (20 mL) was added to a stirred suspension of sodiumhydride (488 mg, 12.2 mmol) in tetrahydrofuran (10 mL) at 0° C. undernitrogen. After stirring for 10 minutes n-butyl lithium (1.6 M inhexanes; 7.3 mL, 11.6 mmol) was added dropwise over 2 minutes thenstirring was continued for a further 10 minutes. A solution of4-bromomethyl-biphenyl (Intermediate 1, 3.00 g, 12.2 mmol) intetrahydrofuran (6 mL) was added dropwise over 10 minutes and theresulting solution stirred at 0° C. for 1.5 hours. 6 M Hydrochloric acid(15 mL) was added; then the crude reaction mixture was extracted withdiethyl ether (3×50 mL). The organic phases were combined, washed withbrine (50 mL), dried (MgSO₄) then the solvent evaporated under reducedpressure. The residue was purified by column chromatography on silicagel (1:20 diethyl ether: cyclohexane) to give the title compound (1.37g, 38%) as a yellow solid. LC/MS: 3.78 min; z/e 342, calcd (M+NH₄) 342.¹H NMR (400 MHz: CDCl₃): 7.55 (2H), 7.50 (2H), 7.43 (2H), 7.32 (1H),7.25 (2H), 3.34 (2H), 2.95 (4H), 1.45 (9H).

Intermediate 3: tert-Butyl5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-oxopentanoate

A solution of 5-biphenyl-4-yl-3-oxo-pentanoic acid tert-butyl ester(13.7 g, 42.4 mmol) in dimethylformamide (10 mL) was added dropwise over20 min to a stirred suspension of sodium hydride (60% mineral oilsuspension; 1.78 g, 44.4 mmol) in dimethylformamide (10 mL) at 0° C.under nitrogen. After stirring for 20 min(2-bromoethoxy)-t-butyldimethylsilane (10.0 g, 46.4 mmol) was addeddropwise over 20 min at 0° C. then the reaction heated to 70° C. for 2.5h. On cooling to room temperature the reaction was quenched by carefuladdition of water (5 mL) then the volatiles evaporated. The residue waspartitioned between saturated aqueous ammonium chloride solution (200mL) and dichloromethane (200 mL) and the phases separated. The aqueousphase was washed with dichloromethane (3×200 mL) then the organic phasescombined, washed with brine (200 mL), dried (sodium sulfate) and thesolvent evaporated. The residue was chromatographed on silica gel (10%diethyl ether: cyclohexane) to give the title compound (12.1 g, 59%) ascolourless oil which was a mixture of diastereomers. LC/MS: 4.70 min;z/e 483, calcd (M+1) 483. ¹H NMR (400 MHz: CDCl₃): 7.55 (2H), 7.50 (2H),7.40 (2H), 7.35 (1H), 7.25 (2H), 3.60 (2H), 2.95 (3H), 2.20 (1H minor)2.0 (1H major), 1.55 (1H), 1.45 (11H), 0.85 (9H), 0.5 (6H).

Intermediate 4: tert-Butyl5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-hydroxypentanoate

Sodium borohydride (1.05 g, 27.7 mmol) was added portion wise to astirred solution of tert-butyl5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-oxopentanoate(12.1 g, 25.2 mmol) in methanol (80 mL) at 0° C. under nitrogen. Oncompletion of addition stirring was continued for 1.5 h then thereaction was quenched with saturated aqueous ammonium chloride solution(80 mL). The resulting mixture was extracted with diethyl ether (3×200mL) then the organic layers were combined, washed with brine (100 mL),dried (magnesium sulfate) and the solvent evaporated. The residue waschromatographed on silica gel (10% to 50% diethyl ether: cyclohexane) togive the title compound (8.47 g, 69%) as a colourless oil which was amixture of diastereomers. LC/MS: 4.49 min; z/e 485, calcd (M+1) 485. ¹HNMR (400 MHz: CDCl₃): 7.60 (2H), 7.50 (2H), 7.45 (2H), 3.90 (1H minor),3.80 (1H minor), 3.70 (1H major), 3.65 (1H major), 3.25 (1H minor), 3.00(1H major), 2.90 (1H), 2.75 (1H), 2.60 (1H major), 2.55 (1H minor), 1.90(1H), 1.85 (2H), 1.45 (10H), 0.90 (9H), 0.5 (6H).

Intermediate 5: 4-Methoxybenzyl 2,2,2-trichloroethanimidoate

4-Methoxybenzyl 2,2,2-trichloroethanimidoate was prepared using theprocedure of Smith, Amos B. Iii; Qiu, Yuping; Kaufman, Michael; Arimoto,Hirokazu; Jones, David R.; Kobayashi, Kaoru; Beauchamp, Thomas J.“Preparation of intermediates for the synthesis of discodermolides andtheir polyhydroxy dienyl lactone derivatives for pharmaceutical use”—WO0004865.

Intermediate 6: 1,1-Dimethylethyl5-(4-biphenylyl)-2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate

Boron trifluoride etherate (8.0 μL, 65 μmol) was added to a stirredsolution of tert-butyl5-biphenyl-4-yl-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-hydroxypentanoate(7.88 g, 16.3 mmol) and 4-methoxybenzyl 2,2,2-trichloroethanimidoate(6.88 g, 24.5 mmol) in tetrahydrofuran (40 mL) at 0° C. under nitrogen.The reaction was allowed to warm to room temperature at which stirringwas continued for 2 h. A further portion of boron trifluoride etherate(8.0 μL, 65 μmol) was then added and stirring was continued at roomtemperature for a further 2 h. Two further additions of borontrifluoride etherate (8.0 μL, 65 μmol) followed by stirring at roomtemperature for 2 h were carried out before evaporation of the solvent.The residue was chromatographed on silica gel (5% to 10% diethyl ether:cyclohexane) to give the title compound (3.39 g, 34%) as a pale yellowoil which was a mixture of diastereomers. LC/MS: 4.81 min; z/e 605,calcd (M+1) 605. ¹H NMR (400 MHz: CDCl₃): 7.55 (2H), 7.45 (4H),7.35-6.80 (7H), 4.50 (2H), 3.80 (3H), 3.60 (3H), 2.95 (1H), 2.80 (1H),2.65 (1H), 1.85 (4H), 1.45 (9H), 0.85 (9H), 0.5 (6H).

Intermediate 7: 1,1-Dimethylethyl5-(4-biphenylyl)-2-(2-hydroxyethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate

A solution of tetra-n-butylammonium fluoride (1.0 M in THF; 6.2 mL, 6.2mmol) was added dropwise over 15 min to a stirred solution of1,1-dimethylethyl5-(4-biphenylyl)-2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate(3.39 g, 5.61 mmol) in tetrahydrofuran (20 mL) at 0° C. under nitrogen.The reaction was allowed to warm to room temperature at which stirringwas continued for 2 h. The volatiles were evaporated and the residuepartitioned between ethyl acetate (100 mL) and water (100 mL). Thephases were separated and the aqueous layer was washed with ethylacetate (3×100 mL). The organic layers were combined, washed with brine(100 mL), dried (magnesium sulfate) and the solvent evaporated. Theresidue was chromatographed on silica gel (50% to 75% diethyl ether:cyclohexane) to give the title compound (1.6 g, 58%) as a yellow oilwhich was a mixture of diastereomers. LC/MS: 3.98 min; z/e 491, calcd(M+1) 491. ¹H NMR (400 MHz: CDCl₃): 7.55 (2H), 7.45 (4H), 7.30 (5H),6.90 (2H), 4.50 (2H), 3.80 (3H), 3.65 (2H), 2.80 (2H), 2.65 (1H major),2.05 (1H minor), 1.85 (3H), 1.60-1.35 (11H).

Intermediate 8: 1,1-Dimethylethyl5-(4-biphenylyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate

Methanesulfonyl chloride (64 μL, 0.83 mmol) was added in one portion toa stirred solution of 1,1-dimethylethyl5-(4-biphenylyl)-2-(2-hydroxyethyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate(368 mg, 0.751 mmol) and triethylamine (15.4 mg, 209 μL, 1.52 mmol) indichloromethane (2 mL) at room temperature under nitrogen. Afterstirring at room temperature for 1 h the crude mixture was partitionedbetween saturated aqueous citric acid solution (20 mL) anddichloromethane (20 mL). The phases were separated and the organic layerwas evaporated to give the title compound (409 mg, 79%) as a yellow oilwhich was a mixture of diastereomers. LC/MS: 4.08 min; z/e 586, calcd(M+1) 586. ¹H NMR (400 MHz: CDCl₃): 7.50 (6H), 7.25 (4H), 7.15 (1H),6.90 (2H), 4.50 (2H), 4.25 (2H), 3.80 (3H), 3.75 (1H), 2.95 (3H),2.90-2.50 (3H), 2.05 (2H), 1.95-1.65 (2H), 1.55-1.35 (9H).

Intermediate 9: 5-(4-Iodo-phenyl)-3-oxo-pentanoic acid tert-butyl ester

t-butylacetoacetate (1.5 mL, 9.2 mmol) was added dropwise over 2 minutesto a stirred suspension of sodium hydride (60% mineral oil suspension;400 mg, 10.0 mmol) in tetrahydrofuran at 0° C. under nitrogen. Afterstirring for 10 minutes n-butyl lithium in hexane (1.6 M; 6.0 mL, 9.6mmol) was added then stirring continued for a further ten minutes. Theresulting solution was treated dropwise with a solution of 4-iodobenzylbromide (2.97 g, 10.0 mmol) in tetrahydrofuran (4 mL) and then warmed toroom temperature. The reaction was stirred for 40 minutes at roomtemperature and then quenched with 6 M HCl (5 mL). The resulting mixturewas extracted with diethyl ether (3×50 mL). The organic phases werecombined, washed with brine (50 mL) and dried (MgSO₄) then the solventevaporated under reduced pressure. The residue was purified via flashchromatography on silica gel (1:20 to 1:10 ethyl acetate/cyclohexane) togive the title compound (1.88 g, 54%) as a yellow oil. LC/MS: 3.66 min;z/e 375, calcd (M+1) 375. ¹H NMR (400 MHz; CDCl₃): 7.6 (2H), 6.93 (2H),3.33 (2H), 2.85 (4H), 1.45 (9H).

Intermediate 10:1,1-Dimethylethyl2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-5-(4-iodophenyl)-3-oxopentanoate

A solution of 5-(4-iodo-phenyl)-3-oxo-pentanoic acid tert-butyl ester(10.0 g, 26.7 mmol) in dimethylformamide (25 mL) was added dropwise over20 min to a stirred suspension of sodium hydride (60% mineral oilsuspension; 1.12 g, 28.0 mmol) in dimethylformamide (25 mL) at 0° C.under nitrogen. After stirring for 20 min(2-bromoethoxy)-t-butyldimethylsilane (7.03 g, 6.31 mL, 29.4 mmol) wasadded dropwise over 20 min at 0° C. then the reaction heated to 70° C.for 3.5 h. On cooling to room temperature the reaction was quenched bycareful addition of water (2 mL) then the volatiles evaporated. Theresidue was partitioned between saturated aqueous ammonium chloridesolution (150 mL) and dichloromethane (150 mL) and the phases separated.The aqueous phase was washed with dichloromethane (3×150 mL) then theorganic phases combined, washed with brine (150 mL), dried (sodiumsulfate) and the solvent evaporated. The residue was chromatographed onsilica gel (25% diethyl ether: cyclohexane) to give the title compound(10.0 g, 70%) as colourless oil which was a mixture of diastereomers.LC/MS: 4.55 min; z/e 533, calcd (M+1) 533. ¹H NMR (400 MHz: CDCl₃): 7.55(2H), 6.90 (2H), 3.55 (3H), 2.85 (4H), 2.15 (2H minor), 1.95 (2H major),1.40 (9H), 0.85 (9H), 0.5 (6H).

Intermediate 11: 1,1-Dimethylethyl2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-3-hydroxy-5-(4-iodophenyl)pentanoate

Sodium borohydride (0.59 g, 15.6 mmol) was added portion wise to astirred solution of 1,1-dimethylethyl2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-5-(4-iodophenyl)-3-oxopentanoate(7.55 g, 14.2 mmol) in methanol (100 mL) at 0° C. under nitrogen. Oncompletion of addition stirring was continued for 1.5 h then thereaction was quenched with saturated aqueous ammonium chloride solution(100 mL). The resulting mixture was extracted with diethyl ether (3×200mL) then the organic layers were combined, washed with brine (100 mL),dried (sodium sulfate) and the solvent evaporated. The residue waschromatographed on silica gel (25% to 50% diethyl ether: cyclohexane) togive the title compound (5.14 g, 68%) as a colourless oil which was amixture of diastereomers. LC/MS: 4.72 min; z/e 535, calcd (M+1) 535. ¹HNMR (400 MHz: CDCl₃): 7.55 (2H), 6.95 (2H), 3.85-3.55 (3H), 3.30 (1Hminor), 3.00 (1H major), 2.80 (1H), 2.65 (1H), 2.55 (1H major), 2.50 (1Hminor), 1.95-1.65 (4H), 1.45 (9H), 0.90 (9H), 0.5 (6H).

Intermediate 12: 1,1-Dimethylethyl2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate

Boron trifluoride etherate (5.0 μL, 39 μmol) was added to a stirredsolution of 1,1-dimethylethyl2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-3-hydroxy-5-(4-iodophenyl)pentanoate(5.14 g, 9.63 mmol) and 4-methoxybenzyl 2,2,2-trichloroethanimidoate(4.05 g, 14.4 mmol) in tetrahydrofuran (40 mL) at 0° C. under nitrogen.The reaction was allowed to warm to room temperature at which stirringwas continued for 2 h. A further portion of boron trifluoride etherate(5.0 μL, 39 μmol) was then added and stirring was continued at roomtemperature for a further 2 h. Two further additions of borontrifluoride etherate (5.0 μL, 39 μmol) followed by stirring at roomtemperature for 2 h were carried out before evaporation of the solvent.The residue was chromatographed on silica gel (0% to 10% diethyl ether:cyclohexane) to give the title compound (4.14 g, 66%) as a yellow oilwhich was a mixture of diastereomers. LC/MS: 4.78 min; z/e 655, calcd(M+1) 655. ¹H NMR (400 MHz: CDCl₃): 7.55 (2H), 7.25 (2H), 6.90 (2H),6.80 (2H), 4.55 (1H), 4.35 (1H), 3.80 (3H), 3.65 (1H), 3.55 (1H), 2.95(1H major), 2.80 (1H minor), 2.70 (1H), 2.55 (1H), 1.95-1.60 (4H), 1.45(9H), 0.85 (9H), 0.5 (6H).

Intermediate 13: 1,1-Dimethylethyl2-(2-hydroxyethyl)-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate

A solution of tetra-n-butylammonium fluoride (1.0 M in THF; 7.0 mL, 7.0mmol) was added dropwise over 15 min to a stirred solution of1,1-dimethylethyl2-(2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate(4.14 g, 6.33 mmol) in tetrahydrofuran (25 mL) at 0° C. under nitrogen.The reaction was allowed to warm to room temperature at which stirringwas continued for 2 h. The volatiles were evaporated and the residuepartitioned between ethyl acetate (100 mL) and water (100 mL). Thephases were separated and the aqueous layer was washed with ethylacetate (3×100 mL). The organic layers were combined, washed with brine(100 mL), dried (magnesium sulfate) and the solvent evaporated. Theresidue was chromatographed on silica gel (25% to 50% ethyl acteate:cyclohexane) to give the title compound (2.87 g, 84%) as a yellow oilwhich was a mixture of diastereomers. LC/MS: 3.86 min; z/e 541, calcd(M+1) 541. ¹H NMR (400 MHz: CDCl₃): 7.55-7.25 (4H), 6.90-6.75 (4H),4.55-4.35 (2H), 3.80 (3H), 3.65 (3H), 2.90-2.45 (3H), 1.90-1.60 (4H),1.35 (9H).

Intermediate 14 1,1-Dimethylethyl5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate

Methanesulfonyl chloride (315 μL, 5.91 mmol) was added in one portion toa stirred solution of 1,1-dimethylethyl2-(2-hydroxyethyl)-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate(2.00 g, 3.70 mmol) and triethylamine (1.03 mL, 7.39 mmol) indichloromethane (10 mL) at room temperature under nitrogen. Afterstirring at room temperature for 1 h the crude mixture was partitionedbetween saturated aqueous citric acid solution (40 mL) anddichloromethane (40 mL). The phases were separated and the organic layerwas evaporated to give the title compound (2.3 g, 100%) as a yellow oilwhich was a mixture of diastereomers. LC/MS: 4.00 min; z/e 636, calcd(M+18) 636. ¹H NMR (400 MHz: CDCl₃): 7.60-7.20 (4H), 6.90-6.75 (4H),4.60-4.20 (5H), 3.80 (3H), 2.95 (3H), 2.90-2.45 (3H), 2.10-1.70 (4H),1.40 (9H).

Intermediate 15: 1,1-Dimethylethyl2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate

Potassium phthalimide (0.33 g, 2.2 mmol) was added in one portion to astirred solution of 1,1-dimethylethyl5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate(1.15 g, 1.86 mmol) in dimethylformamide (6 mL) at room temperatureunder nitrogen. The resulting solution was heated at 80° C. for 1 h 45min then cooled to room temperature. The volatiles were evaporated andthe residue partitioned between dichloromethane (50 mL) and water (50mL). The layers were separated and the organic phase evaporated todryness. The residue was chromatographed on silica gel (50% ethylacetate: cyclohexane) to give the title compound (0.26 g, 21%) as ayellow oil which was a mixture of diastereoisomers. LC/MS: 4.29 min; z/e687, calcd (M+18) 687. ¹H NMR (400 MHz: CDCl₃): 7.85 (2H), 7.70 (2H),7.55-7.20 (4H), 6.90-6.75 (4H), 4.55-4.30 (2H), 3.80 (3H), 3.75 (1H),3.65 (2H), 2.80-2.45 (3H), 2.10-1.50 (4H), 1.40 (9H).

Intermediate 16 1,1-Dimethylethyl5-(4-iodophenyl)-2-[2-(3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)ethyl]-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate

3-Methyl-2,4(1H,3H)-pyrimidinedione (0.28 g, 2.2 mmol) was added in oneportion to a stirred suspension of sodium hydride (60% suspension inmineral oil; 80 mg, 2.0 mmol) in dimethylformamide (3 mL) at roomtemperature under nitrogen. The resulting suspension was stirred for 5min then a solution of 1,1-dimethylethyl5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)-2-{2-[(methylsulfonyl)oxy]ethyl}pentanoate(1.15 g, 1.86 mmol) in dimethylformamide (3 mL) was added in oneportion. The resulting solution was heated at 80° C. for 1 h 45 min thencooled to room temperature. The volatiles were evaporated and theresidue partitioned between dichloromethane (50 mL) and water (50 mL).The layers were separated and the organic phase evaporated to dryness.The residue was chromatographed on silica gel (10% methanol:dichloromethane) to give the title compound (0.33 g, 27%) as a yellowoil which was a mixture of diastereomers. LC/MS: 3.87 min; z/e 649,calcd (M+1) 649. ¹H NMR (400 MHz: CDCl₃): 7.55 (2H), 7.25 (2H), 7.10(1H), 6.90-6.75 (4H), 5.70 (1H), 4.40 (2H), 3.85-3.60 (6H), 3.75-2.45(3H), 2.00-1.70 (4H), 1.40 (9H).

Intermediate 172-[2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-iodophenyl)pentanoicacid

Trifluoroacetic acid (5 mL) was added in one portion to a stirredsolution of 1,1-dimethylethyl2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4-iodophenyl)-3-({[4-(methyloxy)phenyl]methyl}oxy)pentanoate(261 mg, 0.390 mmol) in dichloromethane (5 mL) at room temperature undernitrogen. The resulting solution was stirred for 45 min then thevolatiles evaporated to give the title compound (192 mg, 100%) as ayellow solid which was a mixture of diastereomers. LC/MS: 3.32 min; z/e493, calcd (M+1) 493. ¹H NMR (400 MHz: CDCl₃): 7.85 (4H), 7.55 (2H),6.95 (2H), 4.90 (1H), 3.80-3.50 (3H), 2.70-2.20 (3H), 1.85 (2H), 1.55(2H).

Intermediate 18:3-Hydroxy-5-(4-iodophenyl)-2-[2-(3-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl)ethyl]pentanoicacid

Prepared by an analogous reaction to intermediate 17. LC/MS: 2.85 min;z/e 473, calcd (M+1) 473.

1. A compound of formula (I):

wherein: A is C₁₋₆alkyl; B is a bond; D is C₁₋₆alkyl; E is substitutedaryl or substituted or unsubstituted heteroaryl; Q is an optionallysubstituted 5- or 6-membered aryl or heteroaryl ring; X is CR⁷R⁸; Y isCR⁵OR¹¹; R¹ and R^(1′) each independently is H, C₁₋₆alkyl orC₁₋₄alkylaryl; R² is CO₂R¹²; R³ is H, C₁₋₆alkyl or C₁₋₄alkylaryl; R⁴ isoptionally substituted aryl or heteroaryl; Z is a bond; R⁵ and R⁶ eachindependently is H, C₁₋₆ alkyl or C₁₋₄ alkylaryl; R⁷ and R⁸ eachindependently is H, halo, C₁₋₆ alkyl or C₁₋₄ alkylaryl; R¹¹ is H, C₁₋₆alkyl, C₁₋₄ alkylaryl or COR⁵; R¹² is H, C₁₋₃ alkyl, C₁₋₃ alkylaryl orC₁₋₃ alkylheteroaryl; or a pharmaceutically acceptable salt thereof. 2.A compound of formula (I):

wherein: R¹, R^(1′) and R³ each is hydrogen; A-B-D is —CH₂—CH₂—; R² isCOOH; X is CH₂; Y is CH(OH); Z is a bond; E is phenyl substituted by oneor more substituents selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, halogen,C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂, —NHCOC₁₋₆ alkyl,—OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃, —CONR⁵R⁶, —SO₂N(CH₃)₂,—SO₂CH₃, —SCH; fused cycloalkyl or heterocyclic rings, optionallysubstituted with carbonyl groups, unsubstituted heteroaryl; heteroaryloptionally substituted by one or more substituents selected from C₁₋₆alkyl, C₂₋₆ alkenyl, halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino,—N(CH₃)₂, —NHCOC₁₋₆ alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃,—CONR⁵R⁶, —SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups, or fused cycloalkyl orheterocyclic rings optionally substituted with carbonyl groups;substituted nitrogen-containing heterocyclic ring or phenyl substitutedwith an unsubstituted nitrogen-containing heterocyclic ring; whereinheteroaryl is a mono- or bicyclic heterocyclic aromatic ring systemcontaining 1-3 hetero atoms selected from nitrogen, oxygen or sulfur; Qis a 5- or 6-membered aryl or heteroaryl ring optionally substituted byone or more substituents selected from C₁₋₆ alkyl, C₂₋₆ alkenyl,halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂, —NHCOC₁₋₆alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —CONR⁵R⁶, —SO₂N(CH₃)₂,—SO₂CH₃ or —SCH₃ groups; R⁴ is an aryl or heteroaryl group optionallysubstituted by one or more substituents selected from C₁₋₆ alkyl, C₂₋₆alkenyl, halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂,—NHCOC₁₋₆ alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃, —CONR⁵R⁶,—SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups, or by fused cycloalkyl orheterocyclic rings optionally substituted by carbonyl groups, R⁵ and R⁶each is H, C₁₋₆ alkyl or C₁₋₄ alkylaryl; or a pharmaceuticallyacceptable salt thereof.
 3. A compound according to claim 2 or apharmaceutically acceptable salt thereof, wherein E is phenylsubstituted with a fused substituted nitrogen-containing heterocyclicring or phenyl substituted with an unsubstituted nitrogen-containingheterocyclic ring.
 4. A compound according to claim 2 or apharmaceutically acceptable salt thereof, wherein E is phthalimido.
 5. Acompound according to claim 2 or a pharmaceutically acceptable saltthereof, wherein E is heteroaryl substituted by one or more substituentsselected from C₁₋₆ alkyl, C₂₋₆ alkenyl, halogen, C₁₋₆ alkoxy, cyano,hydroxy, nitro, amino, —N(CH₃)₂, —NHCOC₁₋₆ alkyl, —OCF₃, —CF₃, —COOC₁₋₆alkyl, —OCHCF₂, —SCF₃, —CONR⁵R⁶, —SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups,or by fused cycloalkyl or heterocyclic rings optionally substituted withcarbonyl groups.
 6. A compound according to claim 2 or apharmaceutically acceptable salt thereof, wherein Q is unsubstitutedphenyl.
 7. A compound according to claim 2 or a pharmaceuticallyacceptable salt thereof, wherein R⁴ is phenyl or pyrimidinyl, each ofwhich is optionally substituted with one or more substituents selectedfrom C₁₋₆ alkyl, C₂₋₆ alkenyl, halogen, C₁₋₆ alkoxy, cyano, hydroxy,nitro, amino, —N(CH₃)₂, —NHCOC₁₋₆ alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl,—OCHCF₂, —SCF₃, —CONR⁵R⁶, —SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups.
 8. Apharmaceutical composition, which comprises a compound according toclaim 1 and a pharmaceutically acceptable carrier.
 9. A pharmaceuticalcomposition, which comprises a compound according to claim 2 and apharmaceutically acceptable carrier.
 10. A method for treatment ofchronic obstructive pulmonary disease (COPD), which comprisesadministering a compound according to claim 1 or a pharmaceuticallyacceptable salt thereof to a human subject in need thereof.
 11. A methodfor treatment of chronic obstructive pulmonary disease (COPD), whichcomprises administering a compound according to claim 2 or apharmaceutically acceptable salt thereof to a human subject in needthereof.
 12. The compound according to claim 1, wherein: R¹, R^(1′) andR³ each is hydrogen; A-B-D is —CH₂—CH₂—; R² is COOH; X is CH₂; Y isCH(OH); and Z is a bond.
 13. A compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein each substituted arylor substituted heteroaryl as defined in E is substituted by one or moresubstituents selected from: C₁₋₆ alkyl, C₂₋₆ alkenyl, halogen, C₁₋₆alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂, —NHCOC₁₋₆ alkyl, —OCF₃,—CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃, —CONR⁵R⁶, —SO₂N(CH₃)₂, —SO₂CH₃,—SCH₃; fused cycloalkyl or heterocyclic rings optionally substitutedwith carbonyl groups, unsubstituted heteroaryl; heteroaryl optionallysubstituted by one or more substituents selected from C₁₋₆ alkyl, C₂₋₆alkenyl, halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂,—NHCOC₁₋₆ alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃, —CONR⁵R⁶,—SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups, or fused cycloalkyl orheterocyclic rings optionally substituted with carbonyl groups; orsubstituted nitrogen-containing heterocyclic ring or phenyl substitutedwith an unsubstituted nitrogen-containing heterocyclic ring; whereinheteroaryl is a mono- or bicyclic heterocyclic aromatic ring systemcontaining 1-3 hetero atoms selected from nitrogen, oxygen or sulfur.14. The compound according to claim 1, wherein aryl as defined in E isphenyl.
 15. The compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, wherein E is phenyl substituted with a fusedsubstituted nitrogen-containing heterocyclic ring or phenyl substitutedwith an unsubstituted nitrogen-containing heterocyclic ring.
 16. Thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein E is phthalimido.
 17. The compound according to claim 1or a pharmaceutically acceptable salt thereof, wherein E is heteroarylsubstituted by one or more substituents selected from C₁₋₆ alkyl, C₂₋₆alkenyl, halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂,—NHCOC₁₋₆ alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃, —CONR⁵R⁶,—SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups, or by fused cycloalkyl orheterocyclic rings optionally substituted with carbonyl groups.
 18. Thecompound according to claim 1, wherein the heteroaryl ring as definedfor Q is a 5- or 6-membered aryl or heteroaryl ring optionallysubstituted by one or more substituents selected from C₁₋₆ alkyl, C₂₋₆alkenyl, halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂,—NHCOC₁₋₆ alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃, —CONR⁵R⁶,—SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups.
 19. The compound according toclaim 1, wherein R⁴ is an aryl or heteroaryl group optionallysubstituted by one or more substituents selected from C₁₋₆ alkyl, C₂₋₆alkenyl, halogen, C₁₋₆ alkoxy, cyano, hydroxy, nitro, amino, —N(CH₃)₂,—NHCOC₁₋₆ alkyl, —OCF₃, —CF₃, —COOC₁₋₆ alkyl, —OCHCF₂, —SCF₃,—CONR⁵R⁶—SO₂N(CH₃)₂, —SO₂CH₃ or —SCH₃ groups, or by fused cycloalkyl orheterocyclic rings optionally substituted by carbonyl groups.